1. Field of the Invention
The present invention relates to a body fluid purification medium and a body fluid purification apparatus using the medium for therapeutic purposes of hepatic insufficiency, autoimmune diseases, renal diseases, myoneural diseases, blood dyscrasia, endocrinopathy, cacochymia, allergies, and rejections upon organ transplantation. Body fluids herein include blood, lymphocytes, ascites and the like, but the following description will be made mainly with reference to the case of blood.
II. Description of the Prior Art
When a humoral or cellular immune response against an antigen of cells or tissues of a patient occurs to produce an autoantibody, a disease is caused or a disease accompanying such an immune reaction is caused. Such a disease is called an autoimmune disease. Since a method for preventing such a diseases has not been established, efforts are being made to reduce production of an autoantibody and inflammation of tissues to a minimum. For this purpose, aspirin, drugs called indomethacin for suppressing inflammation, adrenocortical hormones, or drugs for suppressing an immune reaction, i.e., immunosuppressive agents (e.g., imuran, endoxan, or methotrexate) are used. In general, administration of adrenocortical hormones frequently provides good effects. However, when adrenocortical hormones are administered in large amounts over an extended period of time, resistance against infection is lowered and occurrence of stomach or duodenal ulcers, bone weakening (osteoporosis), atrophy of the adrenal cortex, myonosus, diabetes, or psychoneurosis is cortex, myonosus, diabetes, or psychoneurosis is common. Thereafter, administered amounts and time period must be reduced to a minimum. On the other hand, immunosuppressive agents contain carcinogens and damage the hematopoietic function, causing hepatopathy or digestive organ disease.
Plasma exchange therapy for eliminating certain types of immunoglobulin and immune complex has recently been adopted. Such immunoglobulin and immune complexes are considered to be closely associated with causes and the course of diseases associated with immunological functions, including monoclonal proteinemia, allergies, autoimmune diseases, immunodeficiency, or cancers.
However, in plasma exchange therapy, since all the plasma components are equally eliminated, not only loss of necessary plasma components occurs, but also supply shortage of plasma or plasma preparations and the accompanying problems of serum hepatitis or allergies occur. In view of these problems, it is recommended the plasma of a patient be restored after purification.
The methods of eliminating a pathogenic substance include the cascade method using a membrane filter (Sieberth, H.G., Plasma Exchange, p. 29, F. K. Schattauer, Verlag, Stuttgart-New York, 1980), the double filtration method (Tetsuzo Agishi et al, "Jin to Toseki", 10(3), 475, 1981), the freezing filtration method (L'Abbate, A., et al., Proc. Eur. Dial. Transplant. Assoc., 14, 486, 1977), and the salting-out method (Hiroaki Ooe, "Jinkou Zoki", 14, 472, 1985). Clinical tests of these methods are being performed. However, an ideal plasma fractionator (plasma protein fractionator) has not been obtained. When a plasma replenishing liquid is not used in clinical application, hypoproteinemia develops. Therefore, development of an ideal plasma filter and an adsorption medium capable of selectively adsorbing a specific pathogenic substance in plasma and of purifying the plasma has been strongly desired.
As a blood purification adsorbent, activated carbon, a styrene-divinylbenzene copolymer (AR-I) and a negative ion exchange resin has been proposed as an artificial liver support or an adsorption type artificial kidney.
However, such a substance does not have a capacity for adsorbing proteins of relatively large molecular weights in plasma, and development of an adsorbent of better quality is desired.
Conventional adsorbents intended for this purpose include:
(1) Affinity adsorbents
(2) Organic porous resins such as an acrylic ester porous resin (e.g., "XAD-7" available from Rohm & Haas Co.) or a methacrylic ester porous resin
(3) Ion exchange materials such as carboxymethyl cellulose
(4) Inorganic porous materials such as porous silica or porous alumina
However, an acrylic ester porous resin and carboxymethyl cellulose have poor absorption performance and specificity. They also adsorb albumins in a body fluid. Therefore, these adsorbents cause an abnormal osmotic pressure and cannot be used safely in therapeutic equipment.
Affinity adsorbents are roughly classified into biological and physicochemical affinity adsorbents. Biological affinity adsorbents have excellent adsorption specificity, however, they are expensive due to the use of physiologically active high-molecular weight substances such as ligands (i.e., substances having affinity with target substances). In addition, these biological affinity adsorbents have problems of sourcing, or the manufacture, sterilization, storage, transportation and stability of active life during storage and the like of adsorbents or columns. Furthermore, adverse side effects of other physiological functions other than affinity which appear upon contact with blood must also be considered. When a ligand is released and elutes, since it mostly consists of different types of proteins, the problem of side effects by antigens arises. Prevention of the introduction of endotoxins is also an important problem.
On the other hand, physicochemical affinity adsorbents can be mass-produced and have stable activity. These adsorbents also normally have excellent stability upon contact with blood.
Japanese Patent Disclosure (Kokoku) No. 57-122875 discloses an adsorbent for an immunoglobulin and/or immunoglobulin complex. The adsorbent includes a hydrophobic compound which is bonded with an insoluble support. Japanese Patent Disclosure No. 59-17355 discloses an adsorbent for an autoantibody and/or immune complex. The adsorbent includes an organic low-molecular weight compound containing a hydrophobic compound. The low-molecular weight compound is bonded with a porous substance having silanol groups on its surface. Examples of hydrophobic compounds include those having aromatic rings, nitrogen-containing 6-membered rings, nitrogen-containing 5-membered rings, polyvalent nitrogen-containing 6-membered rings, polyvalent nitrogen-containing 5-membered rings, oxygen-containing aromatic rings, sulfur-containing aromatic rings, oxygen-containing heterocylic aromatic rings, and sulfur-containing heterocylic aromatic rings.
However, conventional adsorbents have poor adsorption specificity and performance. In order to perform extracorporeal blood purification therapy when treating a patient, it is preferably that a pathogenic substance be eliminated at a still higher efficiency and adverse influences on the blood be extremely small.